Maruyama Suguru, Imamura Yu, Toihata Tasuku, Haraguchi Ikumi, Takamatsu Manabu, Yamashita Makiko, Nakashima Yuichiro, Oki Eiji, Taguchi Kenichi, Yamamoto Manabu, Mine Shinji, Okamura Akihiko, Kanamori Jun, Nunobe Souya, Sano Takeshi, Kitano Shigehisa, Noda Tetsuo, Watanabe Masayuki
Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Sci. 2025 Jan;116(1):178-191. doi: 10.1111/cas.16373. Epub 2024 Oct 23.
The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.
肿瘤免疫微环境日益成为制定侵袭性癌症治疗方案时的关键考量因素，有证据表明调节性T细胞（Tregs）通过干扰细胞毒性T细胞（CD8+）来减弱抗肿瘤反应。在此，我们推测在弥漫性、非爱泼斯坦-巴尔病毒（EBV）/非微卫星不稳定（MSI）-高的胃食管腺癌（GEAs）中，Tregs（由叉头框蛋白3 [FOXP3]标记）和CD8+细胞比例的预后相关性，与肠道型胃食管腺癌相比，弥漫性胃食管腺癌在临床上表现为更具侵袭性、免疫惰性的肿瘤。在来自303例未经化疗的非EBV/非MSI-高的食管胃交界（EGJ）腺癌的数字图像上，分别计算肿瘤内区域和浸润边缘的FOXP3+/CD8+表达的细胞计数比值。在pStage I-III期肿瘤中，观察到5年EGJ癌特异性生存率与浸润边缘的FOXP3+/CD8+比值之间存在肿瘤组织学的显著修饰预后效应（交互作用p = 0.022；风险比[HR] = 8.47，95%置信区间[CI]为2.04 - 35.19，弥漫性高比值[vs.低比值]；HR = 1.57，95% CI为0.88 - 2.83，肠道型高比值[vs.低比值]）。浸润边缘的高FOXP3+/CD8+比值与RUNX3甲基化相关（p = 0.035），且在RUNX3甲基化的弥漫性组织学亚型中预后较差（5年EGJ癌特异性生存率，高比值为52.3%，低比值为100%，p = 0.015）。来自癌症基因组图谱的多组学数据将CCL28与RUNX3抑制的非EBV/非MSI-高的GEA弥漫性组织学亚型联系起来。我们的数据表明，浸润边缘的高FOXP3+/CD8+比值可能表明通过CCL28的肿瘤免疫逃逸，特别是在RUNX3甲基化的弥漫性组织学亚型中。
